Genetic associations with temporal shifts in obesity and severe obesity during the obesity epidemic in Norway: A longitudinal population-based cohort (the HUNT Study)

Author summary Why was this study done? Our genetic propensities for obesity may make it easier for some and more difficult for others to make healthy lifestyle choices, and for those with genetic predisposition to obesity, today's environment may make these healthy lifestyle choices even more difficult. Genetic predisposition can be measured with a new genetic tool encompassing over 2.1 million genetic variants associated with BMI. How the effects of genetic predisposition to obesity differ as environments are becoming more obesogenic has not been quantified or validated using the genetic tool. What did the researchers do and find? We assessed the changes in the prevalence of obesity according to genetic predisposition over 6 decades in Norway, with increasing and stabilizing prevalence of obesity, using a genome-wide polygenic score (GPS) for BMI and validating by sibling design. Using genetic data from 67,110 individuals aged 13-80 years with repeated height and weight measurements recorded between 1966 and 2019, we found that the prevalence of obesity differed between the participants with the highest and lowest genetic susceptibilities to obesity for all ages at each decade, and the difference increased gradually from the 1960s to the 2000s and then stabilized over the last decade. For example, for 35-year-old men and women, the increase in the prevalence of obesity was 20 percentage points greater for the most genetically predisposed tenth compared with the least predisposed tenth. What do these findings mean? The results indicate that over the past 6 decades, the least genetically predisposed people seem relatively protected from obesity and almost completely protected from severe obesity, whereas the most predisposed people are at risk for both obesity and severe obesity, suggesting that an interplay between genes and an increasingly obesogenic environment could play a role in growing differences in obesity risk between individuals with varying genetic predisposition. The findings from this study highlight the need to identify and to address the specific factors that led to the population-wide increase in obesity. Background Obesity has tripled worldwide since 1975 as environments are becoming more obesogenic. Our study investigates how changes in population weight and obesity over time are associated with genetic predisposition in the context of an obesogenic environment over 6 decades and examines the robustness of the findings using sibling design. Methods and findings A total of 67,110 individuals aged 13-80 years in the Nord-Trondelag region of Norway participated with repeated standardized body mass index (BMI) measurements from 1966 to 2019 and were genotyped in a longitudinal population-based health study, the Trondelag Health Study (the HUNT Study). Genotyping required survival to and participation in the HUNT Study in the 1990s or 2000s. Linear mixed models with observations nested within individuals were used to model the association between a genome-wide polygenic score (GPS) for BMI and BMI, while generalized estimating equations were used for obesity (BMI >= 30 kg/m(2)) and severe obesity (BMI >= 35 kg/m(2)). The increase in the average BMI and prevalence of obesity was steeper among the genetically predisposed. Among 35-year-old men, the prevalence of obesity for the least predisposed tenth increased from 0.9% (95% confidence interval [CI] 0.6% to 1.2%) to 6.5% (95% CI 5.0% to 8.0%), while the most predisposed tenth increased from 14.2% (95% CI 12.6% to 15.7%) to 39.6% (95% CI 36.1% to 43.0%). Equivalently for women of the same age, the prevalence of obesity for the least predisposed tenth increased from 1.1% (95% CI 0.7% to1.5%) to 7.6% (95% CI 6.0% to 9.2%), while the most predisposed tenth increased from 15.4% (95% CI 13.7% to 17.2%) to 42.0% (95% CI 38.7% to 45.4%). Thus, for 35-year-old men and women, respectively, the absolute change in the prevalence of obesity from 1966 to 2019 was 19.8 percentage points (95% CI 16.2 to 23.5, p < 0.0001) and 20.0 percentage points (95% CI 16.4 to 23.7, p < 0.0001) greater for the most predisposed tenth compared with the least predisposed tenth, defined using the GPS for BMI. The corresponding absolute changes in the prevalence of severe obesity for men and women, respectively, were 8.5 percentage points (95% CI 6.3 to 10.7, p < 0.0001) and 12.6 percentage points (95% CI 9.6 to 15.6, p < 0.0001) greater for the most predisposed tenth. The greater increase in BMI in genetically predisposed individuals over time was apparent after adjustment for family-level confounding using a sibling design. Key limitations include a slightly lower survival to date of genetic testing for the older cohorts and that we apply a contemporary genetic score to past time periods. Future research should validate our findings using a polygenic risk score constructed from historical data. Conclusions In the context of increasingly obesogenic changes in our environment over 6 decades, our findings reveal a growing inequality in the risk for obesity and severe obesity across GPS tenths. Our results suggest that while obesity is a partially heritable trait, it is still modifiable by environmental factors. While it may be possible to identify those most susceptible to environmental change, who thus have the most to gain from preventive measures, efforts to reverse the obesogenic environment will benefit the whole population and help resolve the obesity epidemic.